scholarly journals Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

2009 ◽  
Vol 43 (1) ◽  
pp. 19-27 ◽  
Author(s):  
David M Selva ◽  
Geoffrey L Hammond
Keyword(s):  
Thyroid Hormones ◽  
Hepg2 Cells ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hormone Binding ◽  
Metabolic State ◽  
Hepatocyte Nuclear Factor 4Α

Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4α (HNF-4α) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4α levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4.3 kb human SHBG transgene under the control of its own 0.8 kb promoter sequence. Thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T4 treatment of HepG2 cells for 5 days increased HNF-4α mRNA and HNF-4α levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T3 along with increased hepatic HNF-4α levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T4 treatment, but a 4-day pre-treatment with T4 resulted in a robust response that was prevented by co-treatment with HNF-4α siRNA, or by blocking the β-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4α gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4α levels in hepatocytes.

scholarly journals Hepatocyte nuclear factor 4α regulates the expression of intestinal epithelial Na+/H+ exchanger isoform 3

2018 ◽  
Vol 314 (1) ◽  
pp. G14-G21 ◽  
Author(s):  
Saminathan Muthusamy ◽  
Jong Jin Jeong ◽  
Ming Cheng ◽  
Jessica A. Bonzo ◽  
Anoop Kumar ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Core Promoter ◽  
Epithelial Cell Line ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Intestinal Epithelial ◽  
Hepatocyte Nuclear Factor ◽  
Mobility Shift ◽  
Protein Levels ◽  
Hepatocyte Nuclear Factor 4Α

Na+/H+ exchanger isoform 3 (NHE3) plays a key role in coupled electroneutral NaCl absorption in the mammalian intestine. Reduced NHE3 expression or function has been implicated in the pathogenesis of diarrhea associated with inflammatory bowel disease (IBD) or enteric infections. Our previous studies revealed transcriptional regulation of NHE3 by various agents such as TNF-α, IFN-γ, and butyrate involving transcription factors Sp1 and Sp3. In silico analysis revealed that the NHE3 core promoter also contains a hepatocyte nuclear factor 4α (HNF-4α) binding site that is evolutionarily conserved in several species suggesting that HNF-4α has a role in NHE3 regulation. Nhe3 mRNA levels were reduced in intestine-specific Hnf4α-null mice. However, detailed mechanisms of NHE3 regulation by HNF-4α are not known. We investigated the regulation of NHE3 gene expression by HNF-4α in vitro in the human intestinal epithelial cell line C2BBe1 and in vivo in intestine-specific Hnf4α-null ( Hnf4αΔIEpC) and control ( Hnf4αfl/fl) mice. HNF-4α knockdown by short interfering RNA in C2BBe1 cells significantly decreased NHE3 mRNA and NHE3 protein levels. Gel mobility shift and chromatin immunoprecipitation assays revealed that HNF-4α directly interacts with the HNF-4α motif in the NHE3 core promoter. Site-specific mutagenesis on the HNF-4α motif decreased, whereas ectopic overexpression of HNF-4α increased, NHE3 promoter activity. Furthermore, loss of HNF-4α in Hnf4αΔIEpC mice decreased colonic Nhe3 mRNA and NHE3 protein levels. Our results demonstrate a novel role for HNF-4α in basal regulation of NHE3 expression. These studies represent an important and novel target for therapeutic intervention in IBD-associated diarrhea. NEW & NOTEWORTHY Our studies for the first time show that hepatocyte nuclear factor 4α directly regulates NHE3 promoter activity and its basal expression in the intestine.

Sex hormone-binding globulin mRNA levels in human uterine endometrium

1994 ◽  
Vol 131 (6) ◽  
pp. 623-629 ◽  
Author(s):  
Ryou Misao ◽  
Naoki Itoh ◽  
Hidehiro Mori ◽  
Jiro Fujimoto ◽  
Teruhiko Tamaya
Keyword(s):  
Mrna Level ◽  
Biological Action ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Mrna Levels ◽  
Hormone Binding ◽  
Secretory Phase ◽  
Uterine Endometrium ◽  
Hormone Binding Protein ◽  
Human Uterine Endometrium

Misao R, Itoh N, Mori H, Fujimoto J, Tamaya T. Sex hormone-binding globulin mRNA levels in human uterine endometrium. Eur J Endocrinol 1994;131:623–9. ISSN 0804–4643 Sex hormone-binding globulin (SHBG) is a specific steroid hormone-binding protein that plays a role in transporting dihydrotestosterone, testosterone and estradiol-17β (E2), altering their concentration in blood and influencing their biological action. Recently it has been reported that immunoreactive SHBG is localized in target tissues and that SHBG mRNA was identified in human endometrial and prostatic cell lines. In the present work, SHBG mRNA was detected in human normal endometrial tissues using Northern blot analysis and polymerase chain reaction. Its level was higher (p < 0.02) in the secretory phase than in the proliferative phase. In the secretory phase, the endometrial SHBG mRNA level was correlated positively with serum E2 and progesterone level (p < 0.05). However, there was a negative correlation between endometrial SHBG mRNA level and serum E2 /progesterone ratio (p < 0.01). These findings suggest that SHBG is synthesized in the uterine endometrium and a part of its synthesis is regulated complexly by sex steroid hormones such as E2 and progesterone. Ryou Misao, Department of Obstetrics and Gynecology, Gifu University School of Medicine, Tsukasamachi-40. Gifu 500, Japan

Expression of sex hormone-binding globulin mRNA in human ovarian cancers

1995 ◽  
Vol 133 (3) ◽  
pp. 327-334 ◽  
Author(s):  
Ryou Misao ◽  
Yoshihito Nakanishi ◽  
Jiro Fujimoto ◽  
Masashi Hori ◽  
Satoshi Ichigo ◽  
...  
Keyword(s):  
Sex Hormone ◽  
Ovarian Tumors ◽  
Sex Hormone Binding Globulin ◽  
Endometrioid Adenocarcinoma ◽  
Mrna Levels ◽  
Hormone Binding ◽  
Sex Steroid Hormone ◽  
Ovarian Cancers ◽  
Hormone Effect ◽  
Benign Ovarian Tumors

Misao R, Nakanishi Y, Fujimoto J. Hori M, Ichigo S, Tamaya T. Expression of sex hormone-binding globulin mRNA in human ovarian cancers. Eur J Endocrinol 1995;133:327–34. ISSN 0804–4643 To know the role of sex hormone-binding globulin (SHBG) in the intracellular steroidal actions in human ovarian cancers, the expression of SHBG mRNA as a substitute for intracellular SHBG expression was investigated in normal ovarian tissues and ovarian tumors. In the present study, we used competitive reverse transcription–polymerase chain reaction–Southern blot analysis to evaluate SHBG mRNA levels. The expression of SHBG mRNA was detected in all normal ovaries and benign and malignant ovarian tumors analyzed. There were no significant differences in the mean SHBG mRNA levels among the three types of tissue. The expression in normal ovaries was significantly higher (p < 0.01) in premenopause, suggesting the predominance of a sex steroid hormone effect on ovarian SHBG synthesis. Relative overexpression of SHBG mRNA was observed in six out of 22 cases (27%) of ovarian cancer (three cases of endometrioid adenocarcinoma, two cases of serous cystadenocarcinoma and one case of mucinous cystadenocarcinoma) in comparison with normal ovaries and benign ovarian tumors. There was no difference in expression among the clinical stages of ovarian cancers. These data suggest that normal human ovaries and ovarian tumors might synthesize SHBG intracellularly, ovarian cancers might conserve an estrogen-associated property via SHBG and the regulation of intracellular SHBG expression might be changed in some cancers. Ryou Misao, Department of Obstetrics and Gynecology, Gifu University School of Medicine, 40 Tsukasamachi, Gifu 500, Japan

Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells

Climacteric ◽  
2008 ◽  
Vol 11 (sup1) ◽  
pp. 41-46 ◽  
Author(s):  
G. L. Hammond ◽  
K. N. Hogeveen ◽  
M. Visser ◽  
H. J. T. Coelingh Bennink
Keyword(s):  
Hepg2 Cells ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Hormone Binding

Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans

1995 ◽  
Vol 132 (5) ◽  
pp. 594-598 ◽  
Author(s):  
Sonia C Dumoulin ◽  
Bertrand P Perret ◽  
Antoine P Bennet ◽  
Philippe J Caron
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Steroid Hormones ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Hormone Binding ◽  
Thyroid Status ◽  
Corticosteroid Binding Globulin ◽  
Hypothyroid Patients ◽  
Hyperthyroid Patients

Dumoulin SC, Perret BP, Bennet AP, Caron PJ. Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone-binding globulin and corticosteroid-binding globulin) in humans. Eur J Endocrinol 1995;132:594–8. ISSN 0804–4643 Sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) levels were evaluated in euthyroid (N = 111), hyper- (N = 58) and hypothyroid (N = 38) men, in pre- and postmenopausal women (study 1) and in hyper- (N = 24) and hypothyroid (N = 15) patients before and after treatment with carbimazole or levothyroxine therapy (study 2). The SHBG levels are increased in hyper- and decreased in hypothyroid patients, whereas CBG levels are increased in hypo- and decreased in hyperthyroid patients. The SHBG levels are higher in women than in men with similar thyroid status. Plasma SHBG levels are correlated positively whereas CBG levels are correlated negatively with free thyroid hormone concentrations in men as well as women. In hypothyroid patients, SHBG concentrations increased (p < 0.01) and CBG concentrations decreased (p < 0.01) during levothyroxine treatment. In hyperthyroid patients, SHBG concentrations decreased (p < 0.01) and CBG concentrations increased (p < 0.01) during antithyroid treatment. The SHBG and CBG concentrations in treated hypo- and hyperthyroid patients were not significantly different from those of euthyroid controls. Our data indicate that SHBG and CBG levels depend on thyroid status. Corticosteroid-binding globulin is an index of thyroid hormone action at the liver level whose changes are opposite to those of SHBG in hyper- and hypothyroidism. Philippe Caron, Service d'Endocrinologie et Maladies Métaboliques, CHU Rangueil, 1 Avenue J Poulhès, 31054 Toulouse Cedex, France

scholarly journals Cell Type-specific Target Selection by Combinatorial Binding of Smad2/3 Proteins and Hepatocyte Nuclear Factor 4α in HepG2 Cells

2011 ◽  
Vol 286 (34) ◽  
pp. 29848-29860 ◽  
Author(s):  
Anna Mizutani ◽  
Daizo Koinuma ◽  
Shuichi Tsutsumi ◽  
Naoko Kamimura ◽  
Masato Morikawa ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Target Selection ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Cell Type ◽  
Specific Target ◽  
Cell Type Specific ◽  
Hepatocyte Nuclear Factor 4Α

Thyroid hormone turnover in patients with small cell carcinoma of the lung

1988 ◽  
Vol 118 (3) ◽  
pp. 460-464 ◽  
Author(s):  
Jens Faber ◽  
Sven Poulsen ◽  
Per Iversen ◽  
Carsten Kirkegaard
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Cell Carcinoma ◽  
Small Cell Carcinoma ◽  
Transit Time ◽  
Mean Transit Time ◽  
Small Cell ◽  
Sex Hormone ◽  
Sex Hormone Binding Globulin ◽  
Hormone Binding

Abstract. Patients with small cell carcinoma of the lung often present with symptoms suggestive of hyperthyroidism i.e. weight loss without anorexia. Consequently [125I]T4 and [131I]T3 turnover was studied using simultaneously iv bolus injection and noncompartmental analysis in 6 patients with untreated small cell carcinoma of the lung and 14 normal subjects of comparable ages. Both T4 and T3 production rates were enhanced, T4 production being in median 135 nmol · day−1 · 70 kg−1 (range 111–200) in patients with small cell carcinoma of the lung vs 98 nmol·day−1 ·70 kg−1 (range 69–134) in controls (P < 0.01), and T3 production being 46 nmol · day−1·70 kg−1 (range 33–65) vs 31 nmol ·day−1 ·70 kg−1 (range 24–45) (P < 0.01). The mean transit time was shortened for both T4 and T3, T4 mean transit time being 5.9 days (3.9–8.0 days) vs 8.3 days (6.1–11.2 days) in controls (P < 0.01), and T3 mean transit time being 0.74 days (0.36–0.98 days) vs 1.03 days (0.81–1.45 days) in controls (P < 0.01). Serum total and free T4 and T3 levels were unchanged. Basal serum TSH levels and the TSH response to iv TRH were also normal. Thyroid-stimulating immunoglobulins were only present in the serum in 1 of 6 patients. Thus, thyroid hormone production seemed under pituitary regulation. The peripheral effect of thyroid hormones was evaluated measuring serum sex hormone binding globulin levels, which were increased to in median 270% (77–310%) (P < 0.01) of that in controls, suggesting some degree of hyperthyroidism in liver tissue. One patient was re-investigated after complete remission, which resulted in normalization of T4 and T3 production and mean transit time, as well as serum sex hormone binding globulin levels. The data demonstrate that patients with untreated small cell carcinoma of the lung have enhanced turnover of thyroid hormones, a pattern quite different from that usually seen in non-thyroidal somatic illness.

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